(a) Field of the Invention
The present invention relates to tetrahydrocyclopentapyrrole derivatives that can be used for preventing or treating peptic ulcer, gastritis or reflux esophagitis, a method for preparing the same, and a pharmaceutical composition containing the same.
(b) Description of the Related Art
The development of a medicine for peptic ulcer has been focused largely on two kinds (control of aggressive factor, and reinforcement of defensive factor), and among them, a representative treatment method is to control aggressive factor. The development trend gradually led to the development of anticholinergic drug and the development of H2 receptor antagonist from the past development of antacid. Currently, a proton pump inhibitor (PPI) is leading the market.
Since Prout discovered in 1884 that a high concentration of hydrochloric acid is secreted from gastric mucosa, studies on the mechanism of acid secretion have been actively progressed during the last 100 years. And, since Belladonna was used as the first antiulcer drug, anticholinergic drugs had been mainly used, and, in 1920, it was found out that gastric acid secretion is stimulated by histamine. And, since the first histamine H2-receptor antagonist Cimetidine (Tagamet®) that inhibits the activity of histamine, which is strong gastric acid secretion-related hormone, on H2 receptor was developed in 1977, various drugs antagonizing the receptors of acid secretion stimulating materials, and histamine H2-receptor antagonist drugs represented by Ranitidine (Zantac®) developed in 1981, Famotidine (Gaster®/Pepcid®) developed in 1985, and the like led the world antiulcer drug markets. And, since Helicobacter pylori was first isolated as gastritis and ulcer-causing bacteria in 1983, combination therapy of proton pump inhibitor or H2 antagonist and chemotherapeutic agent has been developed for eradication thereof.
Recently, there is an increasing demand for drugs having reversible inhibition mechanism among proton pump inhibitors, and the studies thereon are being actively progressed by global pharmaceutical companies. In order to distinguish from the existing PPI drug represented by Omeprazole, reversible proton pump inhibitors are named as potassium competitive acid blocker (P-CAB) or acid pump antagonist (APA).
Meanwhile, the process of ° secretion on the stomach wall had not been found out for a long time. However, recently, it was found out that H+/K+-ATPase in the microsomal fraction of stomach wall cells acts on the H+ secretion in gastro-intestinal tract to change H+ and K+, and the H+/K+-ATPase was named as a “proton pump”. In the body, H+/K+-ATPase secretes H+ that is produced by converting energy obtained by decomposition of ATP abundant in mitochondria into H2O into the gastric cavity. At this time, the conversion of K+ and H+ is conducted at a ratio of 1:1, and the existence of H+/K+-ATPase was confirmed in many animals secreting H+ including human being.
Namely, in the receptors existing on the cell membrane of stomach wall cells, various acid secretion-stimulating material (histamine, acetylcholine, gastrin) bind to cause a series of gastric acid secretion reactions, and in the final process of the reactions, H+/K+-ATPase referred to as a proton pump that discharges H+ and absorbs K+ in the stomach wall cells acts. A compound inhibiting the proton pump to inhibit gastric acid secretion does not have anticholinergic activity or H2 receptor antagonism, is absorbed as an inactive prodrug when absorbed in the body, and is intensively distributed and activated in the secretory tubules of the parietal cells in gastric mucosa, which are the only acid compartment in a human body, and then, blocks the proton pump, which is the final step of gastric acid production, thereby inhibiting gastric acid secretion by a unique and selective mode of activity.
Representative drugs developed to regulate the proton pump include Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, and the like, and since the inhibitory activity of these drugs on gastric acid secretion are more potent and continuous than the conventional drugs, they are currently widely used as a therapeutic agent of peptic ulcer. And, since omeprazole based compounds strongly inhibit gastric acid secretion and simultaneously have gastric mucosa protection effect (cytoprotective activity), they exhibit characteristics of two activities (i.e., offense type and defense type, more strongly inhibit acid secretion in the day time as well as at night than H2 receptor antagonist, and are known to have low recurrence rate.
However, a possibility that a proton pump inhibitor having irreversible activity mechanism may cause inhibition state of gastric acid secretion in the stomach for a long time to form tumor cells due to bacteria growth in the stomach, promotion of expression of proton pump, and increase in gastrin concentration is being suggested, and thus, development of material capable of inhibiting gastric acid secretion for a certain period only when the drug is administered through the development of reversible proton pump inhibitor is on the rise as research project. Revaprazan (Revanex®) of Yuhan Corporation, marketed on January, 2007 is the only drug, and the research and development of antiulcer drugs by worldwide leading pharmaceutical companies are directed towards reversible proton pump inhibitors, and in the future, appearance of new drugs is being anticipated.
As the representative examples of reversible proton pump inhibitors, a pyrrole derivatives are described in WO2007/026916 (Takeda Pharmaceutical Co. Ltd.), pyrrolo[2,3-c]pyridine derivative are described in WO2006/025716 (Yuhan Corp.), and benzimidazole derivatives are described in WO2007/072146 (Pfizer Inc., Japan; Raqualia Pharma Inc.).